Method of healing bone fractures



United States Patent 3,287,219 METHOD OF HEALING BONE FRACTURES Charles J. Nemanick, 7256 S. Roland Drive, Pasadena Hills, M0. N0 Drawing. Filed Aug. 5, 1963, Ser. No. 300,046

8 Claims. (Cl. 16772) This invention relates to an improved method of healing bone fractures and more particularly to a method of treating animals, including human beings, to reduce the time required for healing bone fractures by administering thereto a composition containing fluoride ions.

Among the several objects of the invention may be noted the provision of an improved method of healing bone fractures; the provision of such a method which substantially acceller-ates the bone healing process and reduces the time required for healing bone fractures; the provision of a method of the type described which may be readily carried out through the administration of specified dosages of :an ionizable fluoride compound in convenient dosage form; and the provision of such a. method which is safe, eflective and economical. Other objects and features will be in part apparent and in part pointed out hereinafter.

The invention accordingly comprises the methods hereinafter described, the scope of the invention being indicated in the following claims.

Asis generally recognized, the ingestion of water containing fluoride ions aids in controlling and inhibiting dental caries. However, to date, it has not been established that the ingestion of caries inhibiting quantities of fluoride ions has any effect on the bone healing process. In accordance with the present invention, it has now unexpectedly been found that the healing of bone fractures can be accelerated or expedited through the employment of small critical dosages of fluoride ions. Further, it has been found that the use of larger amounts of fluoride ions not only fails to effect any acceleration in the healing of bone fractures but may even detract from the healing process.

In accordance with the invention, I have found that the administration of from approximately 0.007 to 8.0 milligrams of fluoride ion daily per 70 kilograms of body weight (weight of an aver-age person), preferably from about 0.0175 to 1.0 milligram of fluoride ion per 70 kilograms of body weight, effectively reduces the time required for bone fractures to heal. Expressed on a smaller scale, this is equivalent to 0.1 to 114.28 micrograms of fluoride ion daily per kilogram of body weight. These dosage levels are substantially below the toxic dose of 200 milligrams of fluoride ion in the case of adults and 250 milligrams in the case of children and therefore are entirely safe for human application. I have found that the administration of fluoride ion is effective for accelerating the healing of bone fractures in both human beings and other warm blooded animals, and the expres r sion animals as employed herein is intended to include both human beings and such animals. In the case of rats and monkeys, experimental studies have established that the best results are obtained using a daily dose level of 7.14 micrograms per kilogram 'of body weight (equivalent to 0.5 milligram per 70 kilograms of body weight in human beings), and that this dosage increases the speed of repair of fractures by approximately 30 to 40% in rats and 35 to 39% in monkeys. In the case of dogs, experimental studies have established that the best results are obtained utilizing a daily dose level of 0.25 micro gram per kilogram of body weight (equivalent to 0.0175 milligram per 70 kilograms of body weight in human beings) and that this dosage increases the speed of repair of fractures by approximately 17 to 25% in dogs.

3 ,287,219 Patented Nov. 22, 1966 In carrying out the method 'of the invention, sodium fluoride is generally and preferably employed as the ionizable fluoride compound which provides the fluoride ions. However, other ionizable fluoride compounds such as potassium fluoride, potassium acid fluoride, sodium bifluoride, sodium silicofluoride and calcium fluoride or other fluoride compounds which yield fluoride ions in dilute aqueous solutions, may also be employed. The method of the invention may be carried out through the ingestion of an ionizable fluoride compound either per se or dissolved in water, or maybe carried out by incorporating an ionizable fluoride compound with other components in tablet form for convenient ingestion. Preferably, an ionizable fluoride compound such as sodium fluoride is employed in combination with sodium chloride. In some instances, the employment of sodium fluoride and sodium chloride has been found more beneficial in accelerating the bone healing process than sodium fluoride alone. Additionally, the inclusion of a large proportion of sodium chloride in the compositions of the invention provides an emetic effect in the event an overdosage of the composition is ingested by an adult or child. Thus, if a quantity of fluoride ion approaching the toxic level is ingested,

. the quantity of sodium chloride simultaneously ingested will cause nausea and resultant emetic action thereby avoiding the dangers normally associated with overdoses of toxic materials.

The compositions of the invention are preferably prepared in tablet form for oral administration. In addition to the desired amount of an ionizable fluoride compound such as sodium fluoride, the tablet may include a major proportion of sodium chloride and a small amount, e.g., 0.5% by weight, of a vegetable binder such as starch. It will be understood that other vegetable binders of a di gestible nature may be employed, but starch is preferred since it'also functions as a dispersant and disintegrating agent causing disintegration of the tablet upon contact with water. Thus, various starches such as potato, corn and rice starch may be employed. Other useful binders include methyl and ethyl cellulose.

The amount of sodium fluoride included in the tablets of the invention may be varied with respect to the proportion of sodium chloride. However, as indicated above, a major proportion of sodium chloride should be included to impart the desired emetic action, and in the preferred form of the invention, the proportion of sodium chloride to sodium fluoride is 43:1. It will be understood that this weight proportion may be varied so long as the proportion of sodium chloride is large compared to the proportion of sodium fluoride or other ionizable fluoride compound.

The following examples illustrate the invention.

Example 1 A 1.5 grain tablet of a useful composition of the invention was prepared by homogeneously intermixin-g the following components and tableting in a standard tableting machine:

Weight, mg. Percent by weight Sodium fluoride 2. 21 2. 27 Potato starch 0. 49 0. 50 Sodium chloride 94. 50 97. 23

ment on the bone healing process, the following animal studies were carried'out.

Example 2 In the first study, three groups of Sprague-Dawley rats were divided on the basis of sex and age. Each group included twelve rats, two females and two males thirty days old, two females and two males one hundred days old and two females and two males six months old. The first group was a control group and the animals in this group were maintained on a standard diet and were given food and distilled water ad libitum. The second group was a test group and the animals in this group were given the same diet as the animals in the first group plus a dietary supplement of sodium fluoride given orally, each animal receiving daily 42.8 micrograms per kg. of body weight of fluoride ion. The third group was also a test group and the animals in this group were given the same diet as the animals of the other two groups plus a dietary supplement of the composition of Example 1 (i.e., sodium fluoride plus sodium chloride) orally, each animal receiving daily 42.8 micrograms per kg. of body weight of fluoride ion.

The femur of each rat in all three groups was fractured-under ether anaesthesia and immobilized by means of an intramedular pin. The respective groups of animals were given access to their respective diets and dietary supplements immediately following the fracturing of the bones.

X-rays of the fracture site were taken at regular intervals of time in order to observe the formation and development of callusesJ At the end of the test period of 35 days, the animals of each group were sacrificed, and the femurs excised and examined to determine the size of calluses, quality of union and other factors related to healing.

The examination of the X-rays of the site of fracture showed the beginning of formation of the callus between the tenth and fifteenth day after the tests were initiated. The size of the calluses in the two test groups at this time were found to be slightly larger as compared with the rats of the control group. The subsequent X-ray pictures taken at five day intervals showed that the. size of the calluses of the animals in the two test groups continued to be larger than the animals in the control group. X-rays taken after 25 and 30 days showed that the size of the calluses in the third group (i.e., those receiving the composition of Example 1) was, on the average, slightly larger than the size of the calluses in the second group.

The examination and measurement of the bone at the site of the calluses thirty-five days after fracture gave the following results:

TABLE I.-DIMENSION OF BONE AT THE SITE OF CAL- LUSES IN MM.

Min. Max. Average Control Group:

1-30 days Old 4. 2 8. 9 6. 14 2-100 days old." 3. 8. 8 6. 01 3-6 months old-.. 4. 5 9. 1 6 34 Average 4. 06 8. 93 6. 16

Sodium Fluoride Group:

1-30 days old 5. 3 7. 8 6. 81 2-10[) days old- 4.3 7.2 6.53 3-6 months old 6. 1 7. 6 7. 61

Average 5. 23 7. 53 6. 98

Sodium Fluoride plus Sodium Chloride (Composition of Example 1):

1-30 days old 4. 2 9. 4 7. 31 2-100 days old 6. 0 8. 7 7. 43 3-6 months old..- 5. 4 9. 1 7. 11

Group Aver g 5. 2 9. O6 7. 28

The examination of the union of the fractured bones excised thirty-five days after the beginning of the tests showed a noticeable increase in degree of healing in both tests groups as compared with the control group. These results are summarized in the following table:

TABLE II.EXAMINATION OF THE UNION OF FRACTURED TIBIA 35 DAYS FROM THE DAY OF THE FRACTURE Examination of the data showed that there was a definite increase in the size of calluses at the site of the fractures in the animals of the two test groups as ,well as a slight increase in the speed of formation of callus.

Example 3 The following study was carried out to supplement the roentgenographic studies of Example 2 relative .to the healing of fractures of the femurs of rats. Three groups of Sprague-Dawley rats were used in the study. The first group was a control group and comprised four young, thirty day old, rats and four adult, one hundred day old, rats, all of whom were maintained on a standard diet and given distilled water for drinking. The second group was a test group and comprised four thirty day old rats and four one hundred day old rats, all of whom,

were given a standard diet plus sodium fluoride in their drinking water, each rat consuming daily 42.8 micrograms per kg. of body weight of fluoride ion (equivalent to a daily dosage of 3 mg. of fluoride ion for a human being weighing 70 kg.). The third group also was a test group and comprised four thirty day old rats and four one hundred day old rats, all of whom were given a standard diet plus the composition of Example 1 in their drinking Water, each rat consuming daily 42.8 micrograms per kg. of body weight of fluoride ion (equivalent to a daily dosage of 3 mg. of fluoride ion for a human being weighing 70 kg.).

The femur of each rat in each of the groups was fractured under ether anaesthesia and immobilized by an intramedular pin. Each group of animals was given access to its respective diet immediately following the fracturing of the bones.- One animal from each group was sacrificed on the fourth, fifth, sixth and seventh day after.

pinning. The site of the fracture was microscopically examined to evaluate the degree of bone repair in each of the animals of the test groups and control group.

The overall pattern in the older animals in the test showed the abnormality of calcium deposition in bone which was demonstrated to great extent in the adult animals receiving daily dietary supplements of fluoride ion.

6 classifications as noted below, and twenty fou-r squirrel monkeys. Each animal received daily the amount of fluoride ion indicated in the table below. In each in- Example 4 stance, the fluoride ion was administered in the form of The fomowing tests were conducted to determine 5 the composition of Example 1 dissolved in drinking water. Whether animals showing calcium d i i may l The human equivalent 15 stated in terms of milligrams show renal change, other foci of metastatic calcification P a human belng Welghlng 70 Weight of all and possible hyperplasia of the parathyroid gland. average man).

TABLE I No. of Human Rats Ani- Age Dietary Supplement Equivmals alent,

Group 1:

a 10 6 months Distilled water (Control) 10 do Distilled water plus 7.14 'y/Kg. fluoride ion 0.5 10 .d Distilled water plus 14.28 'y/Kg. fluoride ion. 1 .0 10 do Distilled water plus 71.4 'y/Kg. fluoride ion. .0

days Distilled water (Control) 10 0 Distilled water plus 7.14 'y/Kg. fluoride ion-- 0.5 10 do D stilled water plus 14.28 'y/Kg. fluoride ion- 1 .0 10 do Distilled water plus 71.4 'y/Kg. fluoride ion 5 .0

No. of Human Monkeys Animals Fluoride ion Equivalent,

4 0.1 4 0.2 4 0.5 4 3.0 4 5.0 Group 6 4 Three groups of Sprague-Dawley rats were employed. The first group was a control group composed of two males and two females, twenty-one days old, two males and two females, one hundred twenty days old, and two males and two females, six months old, all of whom were maintained on a standard diet and given distilled water for drinking. The second group was a test group composed of three males and three females, twenty-one days old, three males and three females, one hundred twenty days old, and three males and three females, six months old, all of whom received a standard diet plus a supplement of sodium fluoride equivalent to a daily dose of 42.8 micrograms per kg. of body weight of fluoride ion. The third group was a test group composed of three males and three females, twenty-one days old, three males and three females, one hundred twenty days old, and three males and three females, six months old, all of whom received a standard diet plus a supplement of the composition of Example 1 equivalent to a daily dose of 42.8 micrograms per kg. of body weight of fluoride ion. The animals of both test groups were maintained on the stated daily dose of fluoride ion for a period of ninety days. Two animals from each age group, one male and one female, of each of the control and .test groups were sacrificed at the end of the experimental period and the vital organs microscopically examined.

The microscopic examination of the soft tissues of the rats of the control and test groups showed very little alteration in any of the tissue examined. The parenchymatous structures of the control and test groups generally showed very little congestive alteration. There was some minimal interstitial edema and congestion, but the kidneys, themselves, the other tissues, the endocrine structures such as parathyroid, pancreatic tissues, mucussecreting glands, and the adrenals showed no evidence of hyperplasia or any significant changes that could be attributed to the ingestion of sodium fluoride or the combination of sodium fluoride and sodium chloride at a daily dose level of 42.8 micrograms per kg. of body weight of fluoride ion.

Example 5 An expanded study was conducted employing eighty Sprague-Dawley rats, divided into two groups and eight The left femur of each of the rats and monkeys was fractured with the animal under ether anaesthesia. The fractures were performed by means of a specially designed stainless steel hook with a handle, the hook being inserted through the skin and muscle and placed immediately below the shaft of the bone at its approximate center. By pulling the handle of the hook up and applying a downward pressure of two fingers to the leg on the sides of the hook, a reasonably uniform fracture was obtained. Immediately following the fracturing of the bones, intramedular pins were inserted.

All animals were maintained in air-conditioned premises with substantially uniform temperature and humidity conditions. The daily water consumption of the animals was established at the beginning of the test and then at regular intervals of time. The solutions of the composition of Example 1 used for the test groups were prepared so as to permit each animal to consume the indicated amount of fluoride ion daily.

In order to determine the rate of healing of the fractures, X-ray pictures of the site of fracture of each rat and monkey were taken at five-day intervals following the fracture of the femur. The X-ray pictures were analyzed for the appearance of periostal reaction, formation of primary calluses and formation of the final callus. The fracture site of each rat and monkey was checked at five-day intervals to observe the degree of immobilization of the union. The individual character of the fracture was taken into consideration during the evaluation of the healing of each fracture.

The following measurements were adopted to evaluate the bone-healing processes:

(a) Periostal reaction was noted by observing the first appearance of hazy density on the film in the immediate vicinity of the fracture indicating the beginning of formation of granulation tissue which builds the primary or temporary callus.

(b) Primary bone callus: The passage from the fibrous or temporary callus to the primary bone callus shows considerable overlapping of the two stages. The appearance of the hazy and incomplete outline of the future bony callus was adopted as the onset of the fibrous or temporary callus, the end of this stage being a final outline of the next stage but still not of suflicient density to be regarded as the final callus.

(c) Final callus: As in the case of the transitory were 30% behind the respective .age groups on the lowest fluoride ion dose.

The results for the monkeys, according to the above noted classification, are summarized in the following stage between the primary callus and primary bone table: I

TABLE IV.AVERAGE HEALING TIME OF FEMURS OF MONKEYS [Expressed in days] Appearance of Foci Appearance of Out- Final Formation of of Calcification line of Primary Callus (Lamelar Dose, Callus Bone) Group 'y/Kg Days Percent of Days Percent of Days Percent of Control Control Control As shown, the speed of repair of bone fracture in the test monkeys was considerably increased as compared with the control monkeys. The most pronounced effect was perceived in animals receiving 7.14 microgramsper kg. of body Weight (equivalent to 0.5 milligram per human being weighing 70 kg.). At this dose level, the increase of speed of healing of the bone fractures was *44.45% as compared with the control for appearance of :foci of calcification; 44.11% as compared with the 1 control for appearance of the outline of primary callus TABLE II.--EVALUATION OF BONE REACTION INRATS AS SEEN ON X-RAY PICTURES TAKEN AT 5-DAY INTERVALS EXPRESSED IN PERCENT [6 months old rats Periostal Reaction and Primary Callus Primary Bone Callus Final Callus (Lamelar Bone) Dose 0 20 100 0 0 0 60 0 0 0 0 20 80 100 0 10 90 100 0 0 0 0 0 0 0 10 80 100 0 10 70 100 O 0 0 20 0 0 0 0 20 80 0 10 80 100 0 O 0 20 0 0 0 0 O 20' 6O TABLE TIL-EVALUATION OF BONE R ACTION IN RATS AS SEEN ON X-RAY PICTURES TAKEN AT 5-DAY E IN [30 day old rats] TERVALS EXPRESSED IN PERCENT Periostal Reaction and Primary Callus Dose Primary Bone Callus Final Callus (Lamelar Bone) Control o'ooo coco From the above, it is observed that perostal reaction generally appeared first in the test groups. In these groups, the onset of the periostal reaction was more rapid in the group of young rats'as compared with the group of old rats, whereas in the control group, the onset times were identical. The lower dose' level of fluoride ion (i.e., 7.14 micrograms per kg.) produced faster response than the higher dose levels." Thedevelopment of the primary callus was fairly' similar in the lower two dose levels of both old and young rats, slightly retarded in the upper dose levels of old rats, and considerably retarded in both control groups. The formation of the final bone callus was found'to be completed after five weeks in both the old and young rats at the lowest dose level of fluoride ion and in the intermediate dose in the older rats. The old rats of the control group were 40% behind and the young rats of the control group and 35-39% as compared with the control for final formation of callus.

Five animals of each classification of the groups of rats were selected at random and taken for microscopic examination at the end of the test period. Tissues from all the monkeys were examined in the same fashion.

The tissues examined microscopically included liver,

nificance as far as the ingestion of fluoride ion is concerned.

The examination of the soft tissues of the monkeys of both the control .and test groups showed no histopathological changes attributable to the influence of fluoride ion. The minimal changes observed in the soft tissues of the monkeys in the test groups were similar to the changes observed in the animals of the control group and were probably associated with the effect of the demise of the animals. The bony structure, however, showed that the animals receiving fluoride ion had a much better and further developed callus formation as compared with the control group. The best callus formation was observed in the animals receiving 7.14 micrograms per kg. of body weight of fluoride ion.

Example 6 Example was repeated using as experimental animals fourteen dogs divided into two basic groups as follows:

TABLE I.GROUP 1 10 fracture sites of the dogs was done at seven day intervals.

For the evaluation of the bone-healing processes in the dogs, an arbitrary numerical system was adopted based on the degree of intensity of different stages of bone repair as seen on the X-rays, observations of the disappearance of mobility of the bones at the fracture site and microscopic examination of the fracture site at the end of the test.

The scoring was as follows:

0=No reaction.

Dose of Fluoride ion Weight Actual Human Dog N0. Sex per kg. in kg. Dose, 1 Equivalent, 7

Distilled water (Control) 14. 07 Distilled water (Control) 7. 72 11. 80 1. 18 7. 0 11. 58 1. 158 7. 0 F 5. 68 1. 420 17. 5 6 M 12. 26 3.065 17. 5 7. F. 14.30 7.150 35.0 8 M 10. 90 5. 450 35. 0

GROUP 2 1 F Distilled water (Control) 15. 12 Distilled water (Control) 10. 00 7. 94 0. 794 7. O 16. 00 1. 0 7. 0 9. 53 4. 35. 0 11. 5. 5 35. 0

The dogs in the first group were subjected to a bone healing test while the dogs in the second group were subjected to an osteoporosis test. Each animal received daily the amount of fluoride ion indicated in the above table. In each instance the fluoride ion was administered in the form of the composition of Example 1 dissolved in drinking water.

1=First visualization of the respective reaction.

2=Advanced reaction.

3=Pronounced reaction.

4=Reaction complete and beginning of the next stage of healing.

The results are set forth in the following tables:

TABLE IL-EVALUATION OF BONE REACTIONS IN DOGS AS SEEN ON X-RAY PICTURES TAKEN AT 7-DAY INTERVALS [A. Periostal reaction and beginning of primary callus] Dog No.

Weeks Dose (v/ a) ool-n-uowo FHNOJNHOOM i iot-marinate Control TABLE III.EVALUATION OF BONE REACTIONS IN DOGS AS SEEN ON X-RAY PICTURES TAKEN AT 7-DAY INTERVALS [A. Primary bone callus and beginning of final callus] Dog No.

Weeks Dose (wt/ OQOP-HMHH OOHIRKIW TABLE IV.EVALUATION OF BONE REACTIONS IN DOGS AS SEEN ON X-RAY PICTURES TAKEN AT 7-DAY INTERVALS [0. Final callus (lamelar bone).]

Weeks Dog Dose (-y/kg.)

ODOQ OOOO DQOOOOOO OOQOOOOO COOHHNOQ OOONP-HFOO at the site of fracture was observed in the animals given 0.25 microgram/kg. and 0.5 microgram of fluoride ion between five and eight weeks as compared to ten weeks and over for animals given 0.1 microgram/ kg. of fluoride ion between five and eight weeks as compared to ten weeks and. over for animals given 0.1 microgram/kg. of fluoride ion and the animals of the control group.

X-ray examination of the bones of the dogs in the osteoporosis test group did not show any changes at the end of the experimental period. Also, anticipating the possibility that the osteoporosis symptoms could be of an insflicien-t magnitude to be detected on the X-ray pictures, alkaline phosphatase of the blood serum, total phosphorus and calcium of the urine were determined before the immobilization of the leg and sixty days later. On the basis of these determinations, no significant changes in the alkaline phosphatase content were observed in the serum and no significant changes in the excretion of phosphorous or calcium were observed.

The microscopic examination of the soft tissue of the dogs in the bone-healing test and control groups did not show any significant changes. No abnormal changes were observed in either the bones of the test group or control group. Sections of all of the fracture sites showed normal repair of the fracture site with organization of the osteoid matrix, calcification and lacunar formation with osteoblastic proliferation proceeding in excellent fashion. The osteoid and osseous repair of the dogs which had received 0.25 microgram/kg and 0.5 microgram/kg. of fluoride ion appeared to be slightly advanced as compared to the dogs of the control group and to those receiving 0.1 microgram/kg. of fluoride ion.

The microscopic examination of the soft tissue of dogs in the osteoporosis test group was practically identical with that of the dogs of the bone-healing test, showing no evidence of anydegenera'tion or inflammatory changes. Detailed examination of the decalcified bone structure of the immobilized legs showed intact periosteum and radiating lamelar and bony fragments without any new bone formation or any significant loss of lacunae or osteoblast formation. No evidence of any osteoporosis changes were observed.

In addition to the above described animal tests, the method of the invention has been employed in promoting the healing of bone breaks or fractures in human beings. It has been found that my method yields beneficial results in reducing the time required for healing bone fractures in humans and does not cause any undesirable physiological effects. Thus, the method of the present invention is effective in reducing the healing time of bone fractures in .bOth human beings and animals. While, as

. administering thereto by means of oral administration:

previously mentioned, my method may be carried out by administering fluoride ions in the form of an ionizable fluoride compound, I prefer to employ a combination of fluoride ions and sodium chloride (e.g., the composition of Example 1).

ions alone, but has the added advantage of providing an emetic action in the event an overdosage is'taken.

In view of the above, itvwill :be seenthat the several objects of the invention are achieved and other advantageous result-s attained.

As various changes could be made in the above methods without departing from the scope of the invention, itis intended that all matter contained in the above description shall be interposed as illustrative and not in a limiting sense.

What isclaimed is:

1. The method of promoting the healing of bone fractures in human beings and animals which comprises administering thereto by means of oral administration between approximately 0.1 and 114.28 micrograms of fluoride ion daily per kilogram of body weight.

2. The method-of promoting the healing of bone fractures in human beings and, animals which comprises administering thereto by means of oral administration between approximately 0.1 and 43 micrograms of fluoride ion daily per kilogram of body weight.

3. The method of promoting the healing of 'bone fractures in human being and animals which comprises administering thereto by means of oral administration approximately 7.14 micrograms of fluoride ion daily per kilogram of body weight.

4. Themethod of promoting the healing of bone fractures in human :beings and animals which comprises approximately 0.25 microgram of fluoride ion daily per kilogram of body weight.

5. The method of promoting the healing of bone fractures in human beings which comprises administering thereto by means of oral administration between approximately 0.007 and 8 milligrams of fluoride ion daily daily per 70 kilograms of body weight.

7. The method of promoting the healing of bone fractures in human beings and animals which comprises daily administering thereto by means of oral administration a composition of matter containing a major proportion of sodium chloride and an amount of an ionizable fluoride compound which upon :being dissolved .in water yields between approximately 0.1. and 114.28 micrograms of fluoride ion per kilogram of body weight.

8. The method of promoting the healing of bone frac-.

tures in human beings which comprises daily administering hereto by means or oral administration a com- This combination not only gives slightly better results in the promotion of bone healing and in reducing the healing time as compared to fluoride 13 .position of matter containing a major proportion of sodium chloride and an amount of an ionizable fluoride compound which upon being dissolved in water yields between 0.007 and 8 milligrams of fluoride ion per 70 kilograms of body weight.

References Cited by the Examiner Dental A'bstracts, vol. 6, 1961, p. 729, Bone Density and Flouride Ingestion.

14 Public Health Reports, vol. 66, No. 47, Nov. 23, 1951, Zipkin, 1., Complex Fluorides, pp. 1523-32.

Sax: Handbook of Dangerous Materials, Rheingold Publ. Co. (1951), pp, 177-178.

Zipkin, I. et al.: Journal of Dental Research, vol. 31, pp. 494-5 1952 JULIAN S. LEVITT, Primary Examiner.

M. J. COHEN, Assistant Examiner. 

1. THE METHOD OF PROMOTING THE HEALING OF BONE FRACTURES IN HUMAN BEINGS AND ANIMALS WHICH COMPRISES ADMINISTERING THERETO BY MEANS OF ORAL ADMINISTRATION BETWEEN APPROXIAMETELY 0.1 AND 114.28 MICROGRAMS OF FLUORIDE ION DAILY PER KILOGRAM OF BODY WEIGHT. 